Introduction to Chemotherapy -- Pharm II Exam 2

NCCN evidence blocks categories and definitions

E -- efficacy and regiment agent

S -- safety of regiment/agent

Q -- quality of evidence

C -- consistency of evidence

A -- affordability of regiment/agent

NCCN evidence blocks categories -- more or less blue blocks are better overall?

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cancer: simple definition

uncontrollable cell growth

- malignant cell rapidly proliferate compared to healthy cells

Factors of cancer

Multifactorial

- sex

- age

- race

- genetic predisposition

- environmental carcingogen exposure

most important factor of cancer

environmental exposure

viruses implicated in cancer?

yes

HPV --> cervical cancer

Cancer treatment

25% pts can be cured by surgery and/or radiation alone

the remainder must receive systemic chemo

overall 5-year survival rate of cancer treatment

68%

in general, cancer treatment should be:

1. surgery -- removal of tumor

2. radiation -- shrink tumor

3. chemotherapy -- kill cancer cells or slow growth

goal of treatment (ideal)

achieve a cure (long term, disease-free survival)

- requires eradication of every neoplastic cell... very hard

when a cure is not attainable:

- control the disease to prevent enlargement and spread

- extend survival and maintain quality of life

- treat cancer as a chronic disease for "near normal" existence

Principles of chemotherapy -- objective

- induce apoptosis or a lethal cytotoxic even in cancer cells

- stop tumor growth progression

prinicples of chemo -- general mechanism of action

- target DNA or essential metabolic pathways of cell replication

ideal anticancer drug:

- interferes with process unique to malignant cells

traditional anticancer drugs

lack specificity, affecting all cells (healthy and cancerous) --> many adverse effects

chemotherapy is often dosed by:

Body surface area

Principles of chemotherapy

- surgery and radiation are always preferred to chemo

- primary chemotherapy

- neoadjuvant chemotherapy

- adjuvant chemotherapy (A = after)

primary chemotherapy

- chemotherapy is the primary treatment in pts with advanced cancer for which no alternative treatment exists

ex: hodgkin and non-hodgkin lymphoma

neoadjuvant chemotherapy

- chemotherapy in patients with localized cancer for which alternative localized therapies, such as surgery, exist but which have been shown to be less than completely effective

adjuvant chemotherapy

A = after

- chemotherapy is administered after surgical resection

- goal of chemo is to reduce the incidence of recurrence and to improve overall survival of pts

Combination chemotherapy

- for each cancer, multiple chemotherapy agents are used simultaneously for best results

- cell cycle specific agents: good for rapidly proliferating cancers (e.g. leukemia)

- non-cell cycle agents: better for slower growing cancers but more toxicity

benefits of combo therapy:

- maximal cell killing within a tolerated range of toxicity

- effective against a broader range of cell lines

- may delay and/or prevent development of resistant cancer cell lines

agents with similar toxicities require...

dose reductions when combined

ex: myelosuppression, nephrotoxicity, cardiotoxicity

Cell Cycle

M phase (Mitosis)

- prophase

- metaphase

- anaphase

- telophase

Interphase

- G1 phase: growth/gap phase

- S phase: DNA synthesis phase

- G2 phase: growth/gap phase

G1 phase

gap/growth phase

- generation of enzymes needed for DNA synthesis

G2 phase

gap/growth phase

- DNA double check

- generation of cellular components for mitosis

prophase

- centrosomes begin to form mitotic spindle

metaphase

- chromosomes align in middle of cell

- microtubules attach to centromeres in preparation of separation

anaphase

chromosomes are separated

telophase

- chromosome cluster to opposite sides

- new nuclear membrane forms

there are _____ checkpoints in the cell cycle to assess cells for abnormalities (like mutations in DNA)

3

- G1 checkpoint

- G2 checkpoint

- M phase checkpoint

cell cycle specific proteins

monitor integrity of DNA

- can initiate DNA repair or apoptosis in severe damage

- e.g. p53, chk-1, chk-2

if the p53 gene or other checkpoint proteins become mutated...

damaged cells enter the S phase and mitosis --> mutated cancer cells form with potential drug resistance

alkylating agents/Adducting agents

cell cycle non specific

damage DNA by forming adducts with it

- may be referred to as "cross-linking" agents by formation of cross links with DNA

- form an electrophile intermediate which is then attacked by a nucleophile

types of aklylating cross links

- inter DNA strand cross link

- intra DNA strand cross link

- DNA/protein cross link

- DNA/RNA cross link

cross linnked dna is ....

recognized as damaged during cell-cycle checkpoints --> apoptosis

alkylating agents -- drugs

- cyclophosphamide and ifosfamide

- carmustine

- temozolomide

- platinum coordination complexes (cisplatin, carboplatin)

Cyclophosphanmide and ifosfamide -- MOA

alkylating agents

Cyclophosphanmide and ifosfamide -- metabolism

must be metabolized in the liver to active compounds

- this produces a toxic byproduct = acrolein

Cyclophosphanmide and ifosfamide n-- acrolein elimination

eliminated by the kidneys

- can lead to hemorrhagic cystitis = bladder becomes inflamed, starts bleeding --> hematuria

what medication is given with Cyclophosphanmide and ifosfamide as ppx for hemorrhagic cystitis?

mesna (mesnex)

carmustine (gliadel) -- MOA

alkylating agent (nitrosoureas)

nitrosoureas

- highly lipophilic

- cross blood-brain barrier (MUST cross BBB)

carmustine (gliadel) -- exists as...

a wafer formulation for brain tumors called gliadel wafer

Temozolomide (temodar) -- MOA

- DNA methylating agent (MTIC active metabolite)

Temozolomide (temodar) -- metabolism

prodrug

- spontaneously hydrolyzed to active metabolite MTIC at physiological pH --> MTIC methylates DNA fragments --> apoptosis

Temozolomide (temodar) -- can it cross BBB?

yes: lipophilic and crosses BBB

- used in glioblastoma multiforme

Platinum coordination complexes

- cisplatin

- carboplatin

- oxaliplatin

Platinum coordination complexes -- MOA

covalently binds DNA bases (guanine) and forms DNA cross links --> denatures double helix --> apoptosis

platinum coordination complexes -- ade

- nephrotoxicity --> dose-limiting toxicity is cisplatin

- ototoxicity --> high potential for hearing loss

ppx to reduce risk of nephrotoxicity in platinum coordination complex use

- amifosine (ethyol)

microtubule inhibitors cell cycle specific?

yes: M phase

microtubule inhibitors : MOA

disrupt mitosis (in metaphase; M phase) by interfering with microtubule formation or degradation

2 main classes of microtubule inhibitors

- Vinca alkaloids

- Taxanes

Vinca alkaloid agents:

vincristine (oncovin)

vinblastine (velban)

vinca alkoloids -- MOA

Cell Cycle specific (M phase)

- bind to tubulin (microtubular subunit) --> block ability for tubulin to polymerize and form microtubules --> dysfunctional mitotic spindle --> chromosomes never separate = apoptosis

taxanes -- agents

paclitaxel (abraxane)

taxanes -- MOA

cell cycle specific (M phase).

taxanes hyperstabilize microtubules --> prevents breakdown of mitotic spindle --> cell remains frozen in metaphase = apoptosis

peripheral sensory neuropathy is a toxicity highly associated with:

- vinca alkaloids (vincristine, vinblastine)

- taxans (paclitaxel)

anti-metabolites: cell specific?

Cell specific: S phase

anti-metabolites: MOA

interfere with synthesis of DNA precursors and DNA synthesis

- effects occur during S phase

antimetabolites: 2 cubclasses

1. antifolates (folate analog)

2. purine/pyrimidine analogs

antimetabolites: drugs

- methotrexate

- 6-mercaptopurine (6-MP)

- 5- fluorouracil (5-FU) /capecitabine

antifolates -- class

antimetabolites

antifolates -- MOA

block DNA precursor synthesis

- structurally similar to folic acid

roles of folic acid

- reduced form (FH4) --> methylation reactions needed in thymidylate/purine biosynthesis

- dihydrofolate reductase (DHFR) --> enzyme responsible for the reduction of folic acid into its active form FHR

anti- folates inhibit:

- dihydrofolate reductase (general biosynthesis)

antifolates deplete ....

purine and pyrmidine pools --> preventing DNA synthesis, repair, and RNA transcription

by reducing purine and pyrimidine pools...

the chances of another chemo-drug (that is an analogue of purine/pyrimidine) being incorporated into DNA increases

- antifolates are used concurrently with other antimetabolites (purine/pyrimidine analogs)

Methotrexate -- class

antimetabolite (antifolate)

methotrexate -- MOA

- dihydrofolate reductase (DHFR) inhibitor --> interferes with DNA synthesis, repair and cellular replication

- also has immune modulator and anti-inflammatory properties

methotrexate -- indications

- cancer (ALL, non-hodgkin lymphoma); part of combination regimen

- autoimmune conditions (RA, chrohns, psoriasis)

- ectopic pregnancy (embryo-fetal toxicity/death)

methotrexate: administration

-PO/IV/intrathecal/IM

methotrexate -- dosing

- fatal errors have occurred with daily dose vs weekly dose

- daily dose --> usually oncology - related

- weekly dose --> usually autoimmune related

can methotrexate be used in pregnancy?

no

methotrexate -- dose adjustments

- hepatic

- renal

methotrexate warnings

- hepatotoxicity

- myelosuppression

- mucositis/stomatitis

- pregnancy (embyro-fetal toxicity/death)

antidote for methotrexate od:

Leucovorin

- metabolite of folic acid that does not rely on DHFR

- referred to as "leucovorin rescue"

- sometimes included as part of chemo regimen with high dose MTX

what may MTX be given with to decrease hematological, GI, and side effects?

folic acid

- given daily on non MTX days

6-mercaptopurine (6-MP) -- class

antimetabolite (purine analog)

6-mercaptopurine (6-MP) -- MOA

- inhibits de novo purine synthesis

- acts as a false metabolite and is incorporated into DNA and RNA to inhibit their synthesis

6-mercaptopurine (6-MP) -- indications

- used in conjunction with MTX in ALL

- effective in curing ~90% of childhood cases

6-mercaptopurine (6-MP) -- metabolism

metabolized by xanthine oxidase

- xanthine oxidase inhibitors can be used to treat gout. (allopurinol)

5- fluorouracil (5-FU) -- class

antimetabolite (pyrimidine analog)

5- fluorouracil (5-FU) -- MOA

- prodrug: converd to 5-FdUMP intracellularly

- 5-FdUMP inhibits thymidylate synthase

- decreased thymidine --> imbalance of deoxynucleotides --> decreased DNA synthesis --> apoptosis

5- fluorouracil (5-FU) -- indications

slow growing tumors

what is commonly administered with 5- fluorouracil (5-FU) to enhance its cytotoxic effects?

- leucovorin

5- fluorouracil (5-FU) -- ade

hand-foot syndrome

- tingling, burning, redness, swelling, and blistering on palms and soles

Topoisomerase inhibitors: cell cycle specific?

cell cycle specific: late S/G2 phase

DNA topoisomerases

- enzymes that help relieve torsional strain in supercoiled DNA

topoisomerase I

cutting one strand of DNA

topoisomerase II

cutting both strands of DNA

topoisomerase inhibitors

prevent DNA from becoming relaxed and trap DNA in a supercoiled position

result = overwound DNA until tension tears it apart --> apoptosis

Topoisomerase I inhibitors: drugs

irinotecan, topotecan

Topoisomerase I inhibitors -- MOA

topoisomerase I inhibitor --> leads to overwinding of DNA --> apoptosis

topoisomerase I inhibitors -- ade

- irinotecan can produce severe diarrhea

what can help manage the severe diarrhea of irinotecan

- early onset: atropine (anticholinergic drug) can help manage early onset diarrhea

Topoisomerase II inhibitors -- drugs

etoposide and teniposide

topoisomerase ii inhibitors -- moa

- topoisomerase ii inhibitor --> leads to overwinding of DNA --> apoptosis

topoisomerase ii inhibitors -- adverse effects

- GI distress

- alopecia